This Program Project application represents a comprehensive collaborative effort by six senior investigators in two Departments of the University of Arizona to carry out a systematic investigation for the development of highly opioid receptor selective and efficacious peptide ligands that will provide nonaddictive opioid analgesics, and new modalities for the treatment of pain, drug dependence and opioid withdrawal. We emphasize studies that will provide new insights for the design of peptide, and peptide conjugate structures that will lead to new modalities for treatment of pain and drug abuse. Consortium and local arrangements have been made that will provide the preclinical data that for the first time will lead to human clinical trials for delta agonists. A highly cooperative multi-disciplinary approach involving computer aided drug design, biophysics, asymmetric synthesis, macrocyclic synthesis, binding studies, in vitro and in vivo assays, and examination of second messenger andother aspects of signal transduction has been established. Strong collaborative interactions will be emphasized with the following major specific aims: 1) to further develop a systematic approach to computer aided design of delta opioid receptor potent and selective peptide ligands that have unique profiles of biological activity, are biostable, can penetrate through the blood-brain barrier (BBB), and are highly efficacious agonists with analgesic activity; 2) prodrug approaches, and carrier mediated mechanisms, which favor passage of peptides and peptide conjugates through the BBB will be examined; 3) to utilize site specific mutagenesis, chimeric structures, second messenger studies, etc. in conjunction with modeling of the human clone delta and other opioid receptors to provide new understanding of the structural basis for agonist and antigonist activity of opioid ligands and the mechanisms of action of opioids; 4) to utilize state of the art pharmacological studies including, antisense deoxyribonucleotides, models of nonciception, and physical dependence including self-administration to obtain new insights into the mechanisms of action of biphalin, [Phe6]DPDPE and other ligands that have unique biological activity profiles including unprecedented efficacy enhancement and minimal side effects; 5) to perform the necessary preclinical toxicity studies needed to eventually file an investigator sponsored investigational New Drug Application (INDA) for human trials for DPDPE and biphalin; 6) to comprehensively examine peptide analogues stability, chemical-physical properties, distribution, bioconversion, and pharmacokinetics in relation to their ability to cross the BBB; 7) to utilize core facilities to prepare quantities of compounds needed for in vitro and in vivo bioassays to obtain more potent, efficacious peptides that can cross the BBB; 8) to develop an understanding of the molecular, dynamic and conformational properties of peptides, and peptide conjugate ligands thatmaximize penetration of the BBB.